Inflammatory bowel disease (IBD) comprises two types of chronic intestinal disorders: Crohn's disease (CD) and ulcerative colitis (UC). The hallmark of active IBD is a pronounced infiltration of innate immune cells (neutrophils, macrophages, dendritic cells, and natural killer T cells) and adaptive immune cells (B cells and T cells) into the lamina propria. Naïve and effector/memory T cells have distinct repertoires of trafficking ligands and receptors that restrict their ability to interact with specialized microvessels in different anatomical compartments. Consequently, they have distinct patterns of migration.
T cells that become activated in mesenteric lymph nodes and Peyer's patches become “gut-tropic” cells after they start expressing the integrin alpha4beta7. While alpha4beta7 is expressed, at various levels, on peripheral T cells, B cells, natural killer cells, and eosinophils, as well as on naïve T cells in peripheral blood, alpha4beta7 is most highly expressed on a subpopulation of CD4+CD45RA− memory T cells, which is believed to play a critical role in the pathogenesis of IBD (Abraham and Cho, N Engl J Med. 2009; 61:2066).
The ligand for alpha4beta7 is the addressin mucosal addressin cell adhesion molecule (MAdCAM-1), a member of the immunoglobulin superfamily. This addressin is primarily expressed on the postcapillary venules of the intestinal lamina propria, the mesenteric lymph nodes, and in Peyer's patches; expression is upregulated in the chronically inflamed small and large intestine of subjects with UC and Crohn's disease (Briskin et al, Am J Pathol. 1997; 151:97; Arihiro et al, Pathol Int. 2002; 52:367).
The importance of alpha4beta7-MadCAM-1 interactions for memory lymphocyte homing to the gut have been shown in preclinical models as well as in man. Tysabri®, a monoclonal antibody targeting the alpha4 component of the alpha4beta1 and alpha4beta7 heterodimeric receptors, significantly improved symptoms in a population of active Crohn's disease subjects (Sandborn et al, N Engl J Med 2005; 353:1912; Targan et al, Gastroenterology 2007; 132:1672). MLN0002, a humanized monoclonal antibody specifically targeting alpha4beta7, was shown to induce disease remission in both UC and Crohn's disease subjects (Feagan et al, Clin Gastroenterol Hepatol. 2008; 6:1370; Feagan et al, N Engl J Med. 2005; 352:2499).
Both of these agents, however, present certain drawbacks. Development of progressive multifocal leukoencephalopathy (PML) in subjects treated with Tysabri® is likely due to inhibition of leukocyte trafficking to the brain. Moreover, MLN0002 induced strong immune responses that contributed to early clearance of the antibody resulting in loss of efficacy. This, together with the potential for severe functional consequences of surgery and drawbacks for other agents used in treating IBD, calls for the development of new therapeutic modalities in IBD.